Residue 67 in the DRbeta1*0101 and DRbeta1*0103 chains strongly influences antigen presentation and DR-peptide molecular complex conformation.
Two closely-related molecules, DR(alpha,beta1*0101) and DR(alpha,beta1*0103), whose beta chains only differ by three amino acids at positions 67, 70, and 71, and six intermediate molecules obtained by site-directed mutagenesis were used to ascertain the respective roles of the three polymorphic residues. Substitutions at positions 70 (D-->Q), 71 (E-->R) and 67 (I or L-->F) strongly affected HA 306-318-specific T-cell recognition. The consequences of the substitution of residue 67 by a phenylalanine depended on the modified HLA-DR molecule. Although this substitution completely inhibited peptide-specific DR1-restricted T-cell recognition, its manifestations on the DR103-restricted T-cell response were variable (abolishing proliferation of some cell lines and not others), no matter what the peptide presented was (HA 306-319 or HIV P25 peptides). We also observed that inhibition of the proliferation of an alloreactive anti-DR103 T-cell clone, caused by a substitution at position 70, was completely cancelled by substitution of residue 67 by a phenylalanine. The observations based on functional experiments, thus, suggest that residue 67 plays an important role in determining conformation of the peptide presented to the T cells. Molecular modeling was used to predict changes induced by amino acid substitutions and highly supports functional data. Substitution of residue 67 by a phenylalanine could have repercussions on the structure of HLA-DR molecule/peptide complexes and affect T-cell recognition.
L'Faqihi
F E
FE
INSERM U395, CHU Purpan, Toulouse, France.
Praud
C
C
Yassine-Diab
B
B
Enault
G
G
Lakhdar-Ghazal
F
F
de Préval
C
C
Coppin
H
H
D000328:Adult; D000818:Animals; D017951:Antigen Presentation; D001665:Binding Sites; D002455:Cell Division; D002461:Cell Line, Transformed; D002470:Cell Survival; D002478:Cells, Cultured; D000090266:Chromobox Protein Homolog 5; D002999:Clone Cells; D005973:Glutamine / Q000235:genetics / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007532:Isoleucine / Q000235:genetics / Q000276:immunology; D007930:Leucine / Q000235:genetics / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000276:immunology*; D010649:Phenylalanine / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
C000715594:CBX5 protein, human; D015798:HLA-DR1 Antigen; D010455:Peptides; D007532:Isoleucine; D005973:Glutamine; D000090266:Chromobox Protein Homolog 5; D010649:Phenylalanine; D007930:Leucine